Pipeline analysis of a vaccine candidate portfolio for diseases of poverty using the Portfolio-To-Impact modelling tool

Introduction

The Special Programme for Research and Training in Tropical Diseases (TDR) recently developed a new modelling tool, called Portfolio-to-Impact (P2I), that allows users to model the impact of different research portfolios¹. The P2I tool can be used to estimate the costs of moving a portfolio of candidate products for poverty-related and neglected diseases (PRNDs) through the pipeline and the likely launches that would result. It can also help to identify potential funding bottlenecks and operational challenges. The modelling tool, which is deterministic, uses Excel based software to estimate the “minimum funding needs to accelerate health product development from late stage preclinical study to phase III clinical trials” and to “visualize potential product launches over time¹.”

To the best of our knowledge, the first published use of the tool was by Young and colleagues². These researchers first conducted a pipeline portfolio review to identify current candidates in the pipeline for 35 PRNDs. They then used the P2I tool to estimate (a) the costs to move these candidates through the pipeline, (b) the likely launches, and (c) the highly needed products that would still be “missing” at the end. As of August 31, 2017, they found 685 PRND product candidates, of which 538 candidates met inclusion criteria for input into the model. Their modelling estimated that it would cost about US$ 16.3 billion (range $13.4–19.8B) to move these candidates along the pipeline, resulting in about 128 (89–160) expected product launches. The study found that “there would be few launches of complex new chemical entities; launches of highly efficacious HIV, tuberculosis, or malaria vaccines would be unlikely².”

The European Vaccine Initiative (EVI), established in 1998 as the European Malaria Vaccine Initiative (EMVI), is a not-for-profit organization that supports the development of effective, affordable and accessible vaccines against diseases of poverty and emerging infectious diseases. To achieve this goal, EVI supports translational vaccine research and development (R&D) spanning from preclinical development through to the establishment of a clinical proof of concept. To date, EVI has supported the development of about 40 vaccine candidates through to early- and mid-stages of clinical development. Initially focussing only on malaria vaccines, in 2009 in the context of a strategic revision EVI broadened its scope and since has built a vaccine portfolio that addresses critical challenges and opportunities in vaccine R&D for a variety of diseases of poverty and emerging infectious diseases.

Currently EVI´s vaccine portfolio comprises around 20 vaccine candidates at different stages of development between late preclinical and mid-stage clinical development. In order to estimate future financing needs required for delivering the EVI portfolio and the potential public health impact of product launches, we conducted an analysis of EVI´s vaccine candidate portfolio using the P2I tool.

Together with similar pipeline portfolio reviews using the P2I tool that are currently being conducted by other product development partnerships (PDPs), the results will inform product developers as well as funders and policy makers regarding future funding needs. The results may also guide future investment priorities to maximise the chances of developing products for diseases that are missing urgently needed health products.

Methods

In this section, we describe the four key steps in this analysis, which are summarized in Figure 1. We do not describe the development of the first version of the P2I tool itself (P2I version 1, or P2I v.1), because this has been previously published¹. The development of a second version of the P2I tool, called P2I version 2 (P2I v.2), has also been previously described². In brief, the model is based on assumptions for costs per phase, attrition rates (probability of success) per phase, and cycle times per phase for four development phases (preclinical to phase III) for 11 different kinds of medical products, called archetypes. The P2I tool is a Microsoft Excel based tool and P2I v.2 uses Microsoft Excel 2016.

Figure 1. Four key phases in the analysis.

Results

(ii) First run of the P2I financing modeling tool, using assumptions from P2I v.2

Estimated costs to move candidates through the pipeline. The total estimated cost to move the 18 candidates along the pipeline to launch would be about US $470 million (Table 5, Figure 2). Just over one third (35%) of the expected costs would be incurred by development of the 8 vaccine candidates for malaria. Development of candidates for placental malaria, Nipah virus, and Zika virus would each account for about 16% of the total costs. The remaining costs would be for development of candidates for leishmaniasis (10% of costs) and shigellosis (7% of costs).

Table 5. Cumulative cost and launch probability per disease based on P2I v.2 model projections.

Disease	Cost (US$, millions)	Cumulative expected launches
Malaria	165.62	0.098
Leishmaniasis	47.77	0.02
Shigellosis, ETEC	33.96	0.07
Nipah	73.96	0.22
Zika	73.96	0.22
Placental malaria	75.08	0.05
Total	470.35	0.69

Figure 2. Cost for vaccine development to launch by disease.

Expected launches. Overall, for all 18 candidates under development, the P2I model estimates that there would be 0.69 cumulative expected launches (we have left all results unrounded). Figure 3 summarizes the expected launches by disease. Table 6 summarizes the estimated cumulative launches by year from 2019-2031 alongside cost estimates. Figure 4 shows the time trends in cumulative costs and cumulative launch probability from 2019-31.

Figure 3. Estimated cumulative launches by disease.

Table 6. Cost and annual launch probability by year.

Year	Cost (US$, millions)	Expected number of launches
2019	44.11794	0
2020	90.39988	0
2021	145.5832	0
2022	199.9804	0
2023	285.8381	0
2024	373.1006	0
2025	413.073	0.44
2026	437.6135	0.52
2027	459.6735	0.52
2028	465.4747	0.67
2029	467.4339	0.67
2030	469.3932	0.67
2031	470.3567	0.69

Figure 4. Cumulative annual costs for vaccine development and annual probability of the number of launches.

Conclusions and discussion

The mission of EVI is to accelerate the development of vaccines for diseases of poverty and emerging infectious diseases. Compared to other PDPs with a narrower focus, for example on a single disease, EVI has a broader scope and consequently a more heterogeneous portfolio, currently comprising 18 active vaccine candidates covering five different diseases/pathogens (malaria, including placental malaria, leishmaniasis, shigella/ETEC, Nipah and Zika viruses). An analysis of EVI´s current vaccine portfolio—providing estimations for future vaccine development costs and expected product launches—was considered important to inform EVI´s decision-making and priority setting, as well as to provide valuable information to global health funders and policy makers.

Overall, using the pre-defined assumptions established in the P2I tool, our modelling resulted in a total estimated cost of about US $470 million for moving all 18 candidates included in the analysis along the pipeline until launch. Of this total amount, just over one third (35%) of the expected costs would be incurred by the development of the eight vaccine candidates for malaria (excluding those for placental malaria). Development of the candidates for placental malaria, Nipah virus, and Zika virus would account for about 16% each of the total costs. The remaining financing would be required for the development of candidates for leishmaniasis and shigellosis (10% and 7% of total costs, respectively).

The re-run (second run) of the P2I model using modified assumptions for phase costs and length based on EVI’s internal data increased the projected portfolio costs by US $46 million up to a total cost of US$ 517 million for all 18 candidates. The main driver of this change in the estimated cost is the increase in expected costs for the unprecedented vaccine candidates (i.e. the eight malaria vaccine candidates, five placental malaria vaccine candidates and two leishmaniasis vaccine candidates). Results for the vaccine candidates for Nipah virus, Zika virus, and shigellosis, ETEC were not affected by the change in these parameters.

The costs that we estimated using the P2I tool are likely to be an underestimate of the true costs. Vaccine development is a reiterative process, meaning that many steps, such as clinical trial phases, will be conducted several times. This process is in contrast to the rationale of the P2I tool, which assumes a straightforward development of product candidates without the reiteration of any particular development steps. For example, very often several phase I trials for a particular antigen are conducted, i.e. multiple trials in which different formulations, different routes of administration or different technology platforms for antigen presentation are being tested and compared. Also, very often several phase I clinical trials are conducted in which a vaccine´s safety is assessed in various age groups in an age-deescalating manner (i.e. the vaccine is tested consecutively in volunteer groups with decreasing age). It is therefore rather unlikely that any vaccine candidate would immediately advance to a phase II clinical trial after the conduct of a single phase I clinical trial only. Consequently, the total costs for the development of the different vaccine candidates in EVI´s portfolio are likely to be significantly higher than those estimated by the P2I tool. In addition, as several phase I or phase II clinical trials are likely to be conducted for the same vaccine (as explained above), due to such “reiterated” phases the overall timelines to reach the market are expected to be longer.

With regards to the estimated future launches, for all 18 candidates under development, the P2I model estimates that there would be 0.69 cumulative expected launches. In the re-run of the model using EVI‘s own internal parameters, thanks to higher success rates at EVI as compared to the P2I tool´s predefined parameters, the launch probability increased for malaria, placental malaria, and leishmaniasis vaccines (from 0.098 to 0.11, from 0.05 to 0.07, and from 0.024 to 0.03, respectively). Directly related to this increased launch probability, the total estimated costs for moving these vaccine candidates through the pipeline increased accordingly. This difference between the estimated future product launches emphasizes that, in order to increase the chances of ultimate success with this kind of product development, it is important to make the product development process technically as efficient as possible, i.e. reducing the attrition rates as much as possible. If attrition rates during product development cannot be reduced, the only other chance of achieving ultimate product launches is to boost the overall number of product candidates in the pipeline, obviously in the end resulting in higher total costs linked to the launch of a single product due to the high costs linked to failed product candidates.

However, rather than looking at the isolated results on likely launches from the analysis of a single organization´s portfolio, a more meaningful estimation will be obtained by conducting a much wider portfolio analysis in which the launch estimation results of the entire global vaccine candidate portfolio are estimated in an integrated, combined manner. Only this kind of “full portfolio” study can provide a reliable prediction of the product success rates on a global level for the next few decades.

The P2I tool has a number of other limitations, which were described in detail by Young et al.² These include: (i) as a static, deterministic model, it does not take into account possible improvements in product development techniques over time (e.g. R&D efficiencies that reduce costs); (ii) the model’s assumptions for costs, attrition rates, and cycle times for phase are based on product development data from across multiple diseases (including non-communicable diseases—the model does not reflect possible differences in R&D parameters between different diseases); and (iii) the model does not include all phases of development (e.g. it excludes drug discovery, basic research, and regulatory review).

In this study, several adaptations to the P2I tool initially were considered with the aim of improving the tool´s usefulness and reliability. First, we considered making adaptations of the assumptions for success rates, costs and cycle times based on EVI’s longstanding experience with conducting studies in resource-limited, low-income settings. Second, we considered making adaptations for the same parameters based on (a) the fast-track clinical development strategy often used by EVI (consisting of a strategy in which the first-in-human evaluation involves a staggered multi-centre phase Ia/b clinical trial resulting in shorter timelines^4,5), and (b) the inclusion of accelerated clinical testing based on controlled human infection models available, for example, for malaria^6,7. Third, in the original proposal we considered including adaptations of the assumptions for costs and cycle times for vaccines that might be eligible for accelerated approval by regulatory authorities, for example the “Expedited Programs for Serious Conditions––Drugs and Biologics” from the US Food and Drug Administration⁸.

In the end, we were able to do one re-run of the P2I model using EVI’s own parameters for success rates and cycle times for phase I clinical trials for unprecedented vaccines (70% and 17.4 months, respectively, compared to 50% and 24 months defined in the original P2I tool for unprecedented vaccines). However, although to date EVI has been involved in the conduct of over 30 clinical trials, data from only a limited number of studies could be used in the analyses conducted. When it came to estimating clinical trial costs, for example, for several trials it was not possible to extract the specific costs for preclinical or clinical trial activities out of the overall study costs.

Concerning the proposed modification of P2I parameters based on accelerated clinical testing using controlled human challenge models and on accelerated approval by regulators, we realized that although these two issues are likely to speed up vaccine development, currently there is not enough evidence/data based on which the P2I parameters could be adapted and analyses be run to assess their impact.

In conclusion, we found that despite the limitations discussed above, the P2I tool was flexible and adaptable enough to be used to study EVI’s portfolio. We believe that the P2I model represents a useful tool to analyze the portfolio of global health products under development. We expect that studies like ours will inform future updates of the model that will further increase its value for product developers, R&D funders, and decision makers.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

The particular vaccine candidates included in this study have been anonymized for intellectual property reasons.